Gene therapy offers the potential to cure or prevent diseases by delivering a therapeutic gene into a host. Gene delivery can effectively stimulate the body's immune response and prevent or control infection. Consequently, gene therapy is under investigation for mesothelioma and other cancer. In this SBIR Phase I proposal, Fifth Base proposes to evaluate and develop a novel charge-reversal amphiphile as carrier of genetic material for mesothelioma cancer cells. We hypothesize that a change in electrostatic interaction between the carrier and DNA will translate to enhanced transfection efficiency and provide a mechanism to deliver the Herpes Simples Virus Thymadine Kinase (HSV-tk) gene. Accordingly, our three specific aims are: [unreadable] [unreadable] SPECIFIC AIM 1: Characterize the charge-reversal amphiphiles and amphiphile/HSV-tk gene supramolecular assemblies. [unreadable] [unreadable] SPECIFIC AIM 2: Evaluate functional interactions amphiphile/DNA supramolecular assemblies with the cells in vitro and delivery of the HSV-tk gene to mesothelioma cancer cells. [unreadable] [unreadable] SPECIFIC AIM 3: Large scale synthesis, sterilization, shelf-live/storage, and initial cytotoxic/toxicology studies. [unreadable] [unreadable] The results from successful completion of these studies will be: (1) the identification of one or two charge-reversal amphiphiles that can deliver the HSV-tk gene to cells; (2) demonstration of a new approach that is a conceptual departure from current gene delivery vectors; and (3) the establishment of commercialization criteria for production and use of material in a Phase II proposal which will focus on evaluation of the charge-reversal amphiphile and HSV-tk gene in an in vivo animal mode. [unreadable] [unreadable] Project Narrative: Patients with Malignant Pleural Mesothelioma (MPM) confront a dismal prognosis. The median survival of patients with mesothelioma is 9-12 months, with extremely low long-term survival over five years regardless of treatment modality. With the use of combination chemotherapy consisting of cisplatin and pemetrexed, the median survival rate is increased by 3-4 months; Most patients are not viable candidates for surgical intervention, and those that elect to have surgery experience mainly palliative benefits. Despite recent advances in surgery, radiotherapy, and chemotherapy, there is no reliably curative treatment for MPM and long-term patient survival is rarely realized. We propose to develop a charge-reversal amphiphile as carrier of genetic material for mesothelioma cancer cells, which may offer the best long-term solution for adults combating this cancer. [unreadable] [unreadable] [unreadable]